The STAT3 inhibitor galiellalactone inhibits the generation of MDSC-like monocytes by prostate cancer cells and decreases immunosuppressive and tumorigenic factors.

ABSTRACT

BACKGROUND: The transcription factor signal transducer and activator of transcription 3 (STAT3) is implicated in cancer drug resistance, metastasis, and immunosuppression and has been identified as a promising therapeutic target for new anticancer drugs. Myeloid-derived suppressor cells (MDSCs) play a major role in the suppression of antitumor immunity and STAT3 is involved in the accumulation, generation, and function of MDSCs. Thus, targeting STAT3 holds the potential of reversing immunosuppression in cancer. This study aims to investigate the effect of the small molecule STAT3 inhibitor galiellalactone on prostate cancer cell- induced generation of MDSCs from monocytes and the effect on immunosuppressive factors and inflammatory cytokines. METHODS: Primary human monocytes were cocultured with prostate cancer cells (DU145, PC3, and LNCaP-IL6) or with conditioned medium (CM) from prostate cancer cells in the presence or absence of the STAT3 inhibitor galiellalactone. Monocytes were analyzed by flow cytometry for an MDSC-like phenotype (CD14+ HLA-DR-/lo ). The secretion and gene expression of immunosuppressive factors and inflammatory cytokines from prostate cancer cells and monocytes were investigated. RESULTS: Galiellalactone blocked the prostate cancer cell-induced generation of MDSC-like monocytes with an immunosuppressive phenotype ex vivo. Monocytes cultured with CM from prostate cancer cells showed increased expression of phosphorylated STAT3. Prostate cancer cells increased the expression of interleukin1ß (IL1ß), IL10, and IL6 in monocytes which was inhibited by galiellalactone. In addition, galiellalactone decreased indoleamine 2,3-dioxygenase gene expression in monocytes. Galiellalactone reduced the levels of IL8 and granulocyte macrophage-colony stimulating factor in prostate cancer cells per se. CONCLUSION: The STAT3 inhibitor galiellalactone may prevent the prostate cancer cell-induced generation of MDSCs and reverse the immunosuppressive mechanisms caused by the interplay between prostate cancer cells and MDSCs. This is a potential new immunotherapeutic approach for the treatment of prostate cancer.